Sialylated Glycan Bindings from SARS-CoV-2 Spike Protein to Blood and Endothelial Cells Govern the Severe Morbidities of COVID-19

Abstract

Consistent with well-established biochemical properties of coronaviruses, sialylated glycan attachments between SARS-CoV-2 spike protein (SP) and host cells are key to the virus’s pathology. SARS-CoV-2 SP attaches to and aggregates red blood cells (RBCs), as shown in many pre-clinical and clinical studies, causing pulmonary and extrapulmonary microthrombi and hypoxia in severe COVID-19 patients. SARS-CoV-2 SP attachments to the heavily sialylated surfaces of platelets (which, like RBCs, have no ACE2) and endothelial cells (having minimal ACE2) compound this vascular damage. Notably, experimentally induced RBC aggregation in vivo causes the same key morbidities as for severe COVID-19, including microvascular occlusion, blood clots, hypoxia and myocarditis. Key risk factors for COVID-19 morbidity, including older age, diabetes and obesity, are all characterized by markedly increased propensity to RBC clumping. For mammalian species, the degree of clinical susceptibility to COVID-19 correlates to RBC aggregability with p = 0.033. Notably, of the five human betacoronaviruses, the two common cold strains express an enzyme that releases glycan attachments, while the deadly SARS, SARS-CoV-2 and MERS do not, although viral loads for COVID-19 and the two common cold infections are similar. These biochemical insights also explain the previously puzzling clinical efficacy of certain generics against COVID-19 and may support the development of future therapeutic strategies for COVID-19 and long COVID patients.

Back to the Basics of SARS-CoV-2 Biochemistry: Microvascular Occlusive Glycan Bindings Govern Its Morbidities and Inform Therapeutic Responses

“…Sharp increases in SpO2 one day after IVM treatment in these three clinical studies contrasted distinctly, far outside 95% confidence intervals, with a flat SpO2 curve under standard treatment. A similar flat SpO2 curve was tracked in several other clinical studies during the first 1-2 weeks of severe or moderate COVID-19 under standard treatment [1]. 2022), as calculated using the Mann-Whitney U test (two-tailed) [88].…”

“…After making its initial attachment to SA, which is ubiquitously distributed on eukaryotic cell surfaces [6][7][8], the virus can then slide over to a host cell receptor for cellular entry, fusion and replication, e.g., via the replication receptor ACE2 for SARS-CoV-2. This is not a new discovery but is rather well-established coronavirus biochemistry known for decades and recently confirmed with multifaceted evidence for SARS-CoV-2 [1]. Ignoring these biochemical fundamentals and assuming that only the replication receptor, ACE2, is of interest for SARS-CoV-2 has led to failures to interpret important pathological sequelae needed to understand clinical symptomatology.…”

“…COVID-19 patients, often with accompanying multiorgan damage and blood clots [1,4]. The attachment of SARS-CoV-2 SP to host cell glycans underlying these morbidities of severe COVID-19 is diagrammed in Figure 1.…”

“…Coronaviruses use a variety of host cell receptors for replication, including DPP4 for MERS, ACE2 for SARS and SARS-CoV-2, and APN for HCoV-229E [ 24 ]. Yet more important for the pathology of SARS-CoV-2 and other coronaviruses is the mechanism by which they initially attach to host cells, which is via glycoconjugate molecules (glycans) on the cell surface [ 1 , 3 , 4 , 6 , 25 , 26 , 27 ]. Sialic acid (SA), the most common terminal monosaccharide (sugar monomer) for vertebrates [ 28 ], is the specific attachment point on host cell glycans for SARS-CoV-2 SP [ 3 , 29 , 30 , 31 ].…”

“…In particular, the well-established bindings of the spike protein (SP) of SARS-CoV-2 and other coronaviruses to surface glycans on blood, endothelial and other host cells and their pathogenic consequences have been largely overlooked. With grounding provided in a recent in-depth review [ 1 ] and dozens of other works, including [ 2 , 3 , 4 , 5 ], key principles of glycan biochemistry essential to understanding and treating COVID-19 and its post-acute sequelae (long COVID) are presented below.…”